Process for preparing dibenzofurans via catalytic heteroannulation

ABSTRACT

The present invention is directed to the synthesis of 2-chloro-cis-[5a(S)-9a(S)-(5a,6,7,8,9,9a-hexahydro)]dibenzofuran-4-carboxylic acid by a stereospecific catalytic heteroannulation synthesis free of undesirable 8-chloro-2,6-methano-2H-3,4,5,6-tetrahydro-1-benzoxocin-10-carboxylic.

BACKGROUND OF THE INVENTION

The tetra and hexahydrodibenzofuran ring systems are common inbiologically active natural compounds (Toth, J. E., et al. J. Org. Chem.1987, 52, 473). Analogs containing these structural features have beenstudied for a variety of indications, such as: antipsychotics (Busch,N., et al. French Patent 2 482 966, 1981), analgesics (Skaletzky, L. L.U.S. Pat. No. 3,317,527, 1967), antitussives (Matharu, S. S., et al. J.Med. Chem. 1977, 20, 197), CNS stimulants (Skaletzky, L. L. U.S. Pat.No. 3,317,527, 1967), and antiemetics (Youssefyeh, R. D., et al. J. Med.Chem. 1992, 35, 895).

Methods for obtaining these ring systems therefore are of considerableinterest. Among the reported compounds which have valuable antiemeticand antipsychotic properties is4-[N-(1-azabicyclo[2.2.2]octan-3-yl)]-2-chloro-[5a,6,7,8,9,9a-hexahydro]dibenzofurancarboxamide.This racemic compound has eight possible stereoisomers, and it has beenreported that4-[N-(1-azabicyclo-[2.2.2]octan-3(S)-yl)]-2-chloro-[5a(S)-9a(S)-(5a,6,7,8,9,9a-hexahydro)]dibenzofurancarboxamideis the most active of the isomers. This is shown as Formula I. ##STR1##

The compound of Formula I is prepared by the reaction of2-chloro-5a,6,7,8,9,9a-hexahydrodibenzofuran-4-carboxylic acid with3-aminoquinuclidine and is described in U.S. Pat. No. 4,863,921.

REPORTED DEVELOPMENTS

Of interest is the synthesis of both enantiomers but the synthesis ofthe S,S enantiomer of2-chloro-cis-(5a,6,7,8,9,9a-hexahydro)]dibenzofuran-4-carboxylic acid isparticularly interesting. Synthesis of these isomers has been reportedusing semipreparative chiral HPLC and classical resolution (Youssefyeh,R. D.; et al J. Med. Chem. 1992, 35, 903).

The above reported synthesis is described by the following Scheme I.##STR2##

This starts with an alkylation of methyl 5-chlorosalicylate with3-bromocyclohexene to afford methyl5-chloro-2-(3'-cyclohexenyl)salicylate (1). After a thermal Claisenrearrangement is performed to afford methyl5-chloro-3-(3'-cyclohexenyl)salicylate (2) an intramolecular cyclizationwith trifluroacetic acid followed by hydrolysis yields racemic2-chloro-cis-(5a,6,7,8,9,9a-hexahydro]-dibenzofurancarboxylic acid andalso results in the formation of a thermo-dynamically favored product,8-chloro-2,6-methano-2H-3,4,5,6-tetrahydro- 1-benzoxocin-10-carboxylicacid. The chiral acids are then obtained by fractional recrystallizationas the R or S α-methylbenzylamine salt. This is a 7 step synthesis.

A second procedure for obtaining2-chloro-cis-[5a(S)-9a(S)-(5a,6,7,8,9,9a-hexahydro)]dibenzofuran-4-carboxylicacid is by the transfer of chirality in a Claisen rearrangements. Thisis described in the following Scheme II. ##STR3##

This is a more direct approach to obtain a stereospecific synthesis anddescribes the Claisen rearrangement with a chiral ether (4).S-2-Cyclohexene-1-ol was obtained by asymmetric ring opening ofcyclohexene oxide. A Mitsunobu condensation between S-cyclohexanol andmethyl 5-chlorosalicylate provided the chiral ether 4. The thermalClaisen rearrangement of 4 afforded 5 in moderate yield along with theproducts of elimination, cyclohexadiene and methyl 5-chloro-salicylate.Acid catalyzed intramolecular cyclization yielded a 3 to 1 mixture ofstructural isomers shown in Scheme II. The benzofuran isomer is thekinetic product and can be converted to the thermodynamically favoredbenzoxocin isomer by treatment with concentrated sulfuric acid asreported earlier (R. D. Youssefyeh et al. J. Med. Chem. 1992, 35, 903).Upon hydrolysis with lithium hydroxide the benzofuran isomerprecipitates out as the lithium salt and is easily separated byfiltration. Acidification of this material yields2-chloro-[5a(S)-9a(S)-(5a,6,7,8,9,9a-hexahydro)]dibenzofuran-4-carboxylicacid (3 S,S) in 5 steps, which is similar to the material obtained byclassical resolution, the structural determination of which was made byX-ray crystallography. The Claisen rearrangement using S-cyclohexanolproceeds in only moderate yield, and one quarter to one third of thechiral material obtained is lost as the benzopyran isomer.

The present invention is directed to the synthesis of2-chloro-cis-[5a(S)-9a(S)-(5a,6,7,8,9,9a-hexahydro)]dibenzofuran-4-carboxylic acid by stereospecificsynthesis to obtain the desired isomer.

SUMMARY OF THE INVENTION

We have discovered that the desired2-chloro-cis-[(5a,6,7,8,9,9a-hexahydro)]dibenzofurancarboxylic acid maybe conveniently prepared substantially free of undesirable8-chloro-2,6-methano-2H-3,4,5,6-tetrahydro-1-benzoxocin-10-carboxylicacid by a catalytic heteroannulation reaction to obtain a cis fusedbenzofuran system.

DETAILED DESCRIPTION

The catalytic heteroannulation synthesis substantially eliminates thebenzoxocine structural isomer and is described by Scheme III below.##STR4##

5-Chlorosalicyclic acid is iodinated in the 3 position withN-iodosuccinamide in DMF and esterified with thionyl chloride inmethanol to afford 7. Condensation of 7 with cyclohexadiene, and using acatalytic system developed by Larock et al. (Larock, R. C.,Berrios-Pena, N., Narayanan, K. J. Org. Chem. 1990, 55, 3447.), methyl2-chloro-[(5a,8,9,9a-tetrahydro)]-dibenzofurancarboxylate (8) can begenerated in one step with the correct substitution. Lithium hydroxidehydrolysis of 8 followed by reduction with 5% palladium on carbon yieldsracemic 2-chloro-(5a,6,7,8,9,9a-hexahydro)]dibenzofurancarboxylic acid 3in 5 steps from 5-chlorosalicylic acid. This approach provides a simpleand direct synthesis of racemic2-chloro-(5a,6,7,8,9,9a-hexahydro)]dibenzofurancarboxylic acid 3 whichmay then be resolved without interference from the formation of thebenzoxocin isomer.

The following reaction examples describe the process of this inventionand are intended to be representative and not to limit the reactionconditions involved.

5-Chloro-3-iodosalicylic Acid (6)

5-Chlorosalicylic acid (20 g, 115.8 mmol) is dissolved in DMF (100 mL).To this solution is added NIS (26.1 g, 116.0 mmol) which causes thereaction to warm up to 60° C. The reaction is stirred at roomtemperature for 20 hours. At this point ethyl acetate (100 mL) is addedand the solution washed with 0.1N HCl (100 mL). The organic phase isthen washed with water (3×100 mL), dried with sodium sulfate andevaporated under reduced pressure to yield 5-yield5-chloro-3-iodosalicylic acid as off-white solid. (mp 160°-163° C.)

Methyl 5-chloro-3-iodosalicylate (7)

Thionyl chloride (30 mL, 411 mmol) is added dropwise to methanol (100mL) in an ice bath. The addition is controlled to hold the temperatureat 25° C. Upon completion of the addition 6 (25 g, 84 mmol) is added andthe reaction heated to reflux for 4 hours. The solids dissolve at firstthen after 2 hours solids start to come out of solution. After 4 hoursTLC (hex:EtOAc; 9:1) shows no starting material. The reaction is cooledin the refrigerator for 12h. The solids formed are filtered washed withwater (30 mL), and dried under vacuum at 27° C. to yield methyl5-chloro-3-iodosalicylate as an off white solid. (mp 143°-145° C.)

2-Chloro-cis-5a,8,9,9a-tetrahydrodibenzofuran-4-methylester (8)

A sample of 7 (5 g, 16 mmol) was treated with palladium(II)acetate (0.18g, 0.8 mmol), tetrabutylammonium chloride (4.5 g, 16 mmol, 1.0 eq),sodium acetate (4.6 g, 56 mmol, 3.5 eq), 1,3-cyclohexadiene (6 g, 82mmol, 5.0 eq), and DMF (32 mL). The reaction was heated for 24 hours at100° C., cooled to room temperature, diluted with toluene (30 mL),washed with ammonium chloride (2×60 mL), dried with magnesium sulfate,and the solvent removed under reduced pressure. A yield of 3.3 g (78%)of product was obtained after trituration of the crude material withhexane. (mp. 90°-93° C.)

2-Chloro-cis-5a,8,9,9a-tetrahydrodibenzofuran-4-carboxylic acid (9)

To a slurry of 8 (3 g, 11.4 mmol) in water (60 mL) is added lithiumhydroxide monohydrate (0.7 g, 16.2 mmol) and the mixture heated to 65°C. When no more starting material remains by TLC (Hex:EtOAc; 9;1), themixture is cooled overnight. The precipitated solids are filtered andthen slurried in ethyl acetate (45 mL). Deionized water (25 mL) is addedto this slurry, which is then acidified with 10% aqueous hydrochloricacid to a pH of 1-2. The layers are separated and the ethyl acetatephase concentrated to dryness to give 2-chloro-cis-5a,8,9,9a-tetrahydrodibenzofuran-4-carboxylic acid (9) as a white solid.(mp 147°-150° C.)

2-Chloro-cis-(5a,6,7,8,9,9a)-hexahydrodibenzofuran-4-carboxylic acid (3)

The acid 9 (6.5 g, 26.0 mmol) is slurried in (200 mL) of ethanol in aParr shaker reaction bottle. 5% Palladium on carbon (0.65 g) is added tothis and the reaction placed on a Parr shaker. The reaction flask isevacuated and flushed with nitrogen three times then flushed withhydrogen twice before being filled to 35 psi with hydrogen. The reactionis run for 2.5 h. The reaction mixture is filtered through a frit andthe catalyst is washed with ethanol (300 mL). The solvent is evaporatedunder reduced pressure, this material is then dissolved in hexane (15mL), cooled to 5° C. and filtered to yield2-chloro-cis-(5a,6,7,8,9,9a)-hexahydrodibenzofuran-4-carboxylic acid (3)as a white solid. (mp 150°-154° C.)

I claim:
 1. A process for the preparation of substantially pure2-chloro-cis-(5a,6,7,8,9,9a-hexahydro)dibenzofuran-4-carboxylic acidby:(a) heating methyl 5-chloro-3-iodosalicylate with 1,3-cyclohexadienein the presence of palladium(II)acetate, tetrabutylammonium chloride andsodium acetate in a polar medium selected from DMF andN,N-dimethylacetamide to obtain2-chloro-cis-5a,8,9,9a-tetrahydrodibenzofuran-4-methylester; (b)hydrolyzing 2-chloro-5a,8,9,9a-tetrahydrodibenzofuran-4-methylester withlithium hydroxide monohydrate to obtain2-chloro-cis-5a,8,9,9a-tetrahydrodibenzofuran-4-carboxylic acid; and (c)reducing 2-chloro-cis-5a,8,9,9a-tetrahydrodibenzofuran-4-carboxylic acidto obtain2-chloro-cis-(5a,6,7,8,9,9a-hexahydro)dibenzofuran-4-carboxylic acidwith 5% palladium on carbon.